A method for continuous flow reaction synthesis of nebivolol hydrochloride
By using a plate-shaped palladium-on-carbon catalyst in a continuous flow reactor and controlling the reaction conditions, the hazards and impurity generation problems of preparing nebivolol hydrochloride in an autoclave were solved, and efficient and safe synthesis of nebivolol hydrochloride was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI SHYNDEC PHARMA HAIMEN CO LTD
- Filing Date
- 2023-11-24
- Publication Date
- 2026-07-03
AI Technical Summary
Existing methods for preparing nebivolol hydrochloride suffer from problems such as high-risk autoclave operation, long reaction time, and the generation of numerous and difficult-to-remove impurities.
A continuous flow reactor was used, with palladium on carbon as the catalyst. The catalyst feed ratio, hydrogen pressure, reaction residence time and temperature were controlled to carry out the hydrogenation reaction. The post-treatment was cooling crystallization and filtration.
The synthesis of nebivolol hydrochloride, characterized by high safety, short reaction time, few side reactions, and high conversion rate, has been achieved, while reducing impurity formation and improving product purity.
Smart Images
Figure CN117567422B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for synthesizing nebivolol hydrochloride via continuous flow reaction. Background Technology
[0002] Nebivolol hydrochloride is a potent and selective third-generation beta-blocker, blocking β1 receptors 290 times more effectively than β2 receptors. In comparison, bisoprolol is 26 times more potent, atenolol 15 times more, and propranolol only 1.9 times more potent under the same conditions. Therefore, nebivolol hydrochloride exhibits higher selectivity, does not cause bronchial or vascular smooth muscle contraction, and has no endogenous sympathomimetic activity. It can be used long-term, maintaining its antihypertensive efficacy even after three years of continuous use, and its efficacy does not decrease due to drug tolerance.
[0003] Traditional preparation techniques for nebivolol hydrochloride, as disclosed in patent US2007 / 149612A1, involve adding N-benzylnebivolol hydrochloride and methanol to a hydrogenation autoclave, starting stirring, purging with nitrogen, introducing hydrogen, and stirring at high temperature for 1–3 hours. After the reaction is complete, the residual N-benzylnebivolol hydrochloride is 0.3–1.0 wt%, impurities (mainly defluorination impurities) are 0.5–1.5 wt%, and the target product is 98.0–99.0 wt%. However, at present, the hydrogenation reaction itself is a high-risk reaction, and due to the long reaction time, defluorination impurities are easily generated. These impurities are difficult to remove in post-processing and purification, affecting the quality and yield of nebivolol hydrochloride products. Summary of the Invention
[0004] The purpose of this invention is to provide a method for synthesizing nebivolol hydrochloride via continuous flow reaction, which solves the problems of high risk, long reaction time, and excessive and difficult-to-remove impurities generated in existing preparation methods.
[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:
[0006] This invention provides a method for the continuous flow reaction synthesis of nebivolol hydrochloride, comprising the following steps:
[0007] (1) A catalyst is packed into the packed bed of a continuous flow fixed bed reactor, hydrogen is introduced into the continuous flow fixed bed reactor, and N-benzylnebirol hydrochloride solution is added to carry out a hydrogenation reaction.
[0008] (2) Collect the liquid after the hydrogenation reaction is completed, and perform post-treatment on the liquid to obtain nebivolol hydrochloride.
[0009] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, the catalyst in step (1) is a sheet-like palladium on carbon.
[0010] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, the mass ratio of N-benzylnebivolol hydrochloride to catalyst in the N-benzylnebivolol hydrochloride solution in step (1) is 1:0.5 to 1:1.2.
[0011] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, the pressure of hydrogen gas introduced in step (1) is 0.8 to 2.0 MPa.
[0012] Preferably, in the method for synthesizing nebivolol hydrochloride via a continuous flow reaction, the flow rate of the N-benzylnebivolol hydrochloride solution in step (1) is 5 to 15 mL / min.
[0013] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, the temperature of the hydrogenation reaction in step (1) is 45-60°C, and the time of the hydrogenation reaction in step (1) is 1-5 min.
[0014] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, the post-treatment in step (2) is cooling crystallization and filtration.
[0015] Preferably, in the method for synthesizing nebivolol hydrochloride via a continuous flow reaction, the cooling crystallization temperature is 15–20°C, and the cooling crystallization time is 0.5–1 h.
[0016] Preferably, in the method for synthesizing nebivolol hydrochloride by continuous flow reaction, step (1) before introducing hydrogen into the continuous flow fixed bed reactor further includes replacing the air in the continuous flow fixed bed reactor with nitrogen.
[0017] Preferably, in the method for synthesizing nebivolol hydrochloride via a continuous flow reaction, the N-benzylnebivolol hydrochloride solution in step (1) is a mixture of N-benzylnebivolol hydrochloride, a straight-chain monohydric alcohol, and water.
[0018] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects:
[0019] This invention achieves the continuous and efficient preparation of nebivolol hydrochloride by controlling the catalyst feed ratio, hydrogen pressure, reaction residence time, and reaction temperature. The synthesis method adopted can realize continuous material feeding reaction, with short reaction time, mild conditions, few side reactions, and high conversion rate. Attached Figure Description
[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.
[0021] Figure 1 This is a schematic diagram of the continuous flow reaction synthesis of nebivolol hydrochloride according to the present invention;
[0022] Figure 2 The reaction diagram for the synthesis of nebivolol hydrochloride from N-benzylnebivolol hydrochloride. Detailed Implementation
[0023] This invention provides a method for the continuous flow reaction synthesis of nebivolol hydrochloride, comprising the following steps:
[0024] (1) A catalyst is packed into the packed bed of a continuous flow fixed bed reactor, hydrogen is introduced into the continuous flow fixed bed reactor, and N-benzylnebirol hydrochloride solution is added to carry out a hydrogenation reaction.
[0025] (2) Collect the liquid after the hydrogenation reaction is completed, and perform post-treatment on the liquid to obtain nebivolol hydrochloride.
[0026] In this invention, the N-benzylnebirol hydrochloride solution in step (1) is preferably a mixture of N-benzylnebirol hydrochloride, a straight-chain monohydric alcohol, and water.
[0027] In this invention, the straight-chain monohydric alcohol is preferably methanol.
[0028] In this invention, the mass-to-volume ratio of the N-benzylnebirol hydrochloride, the straight-chain monohydric alcohol, and the water is preferably 20g:200-300mL:20mL, more preferably 20g:250-300mL:20mL, and even more preferably 20g:300mL:20mL.
[0029] In this invention, the manufacturer of the continuous flow fixed bed reactor in step (1) is preferably Shandong Weijing Chemical Technology Co., Ltd., and the preferred model is VFBXSS0800 or VFBXHS0800.
[0030] In this invention, the catalyst in step (1) is preferably flake-shaped palladium on carbon.
[0031] In this invention, the effective substance content of the catalyst in step (1) is preferably 0.8 to 1.5 wt%, more preferably 1.0 to 1.5 wt%, and even more preferably 1.5 wt%.
[0032] In this invention, the mass ratio of N-benzylnebirolol hydrochloride to catalyst in the N-benzylnebirolol hydrochloride solution in step (1) is preferably 1:0.5 to 1:1.2, more preferably 1:0.8 to 1:1, and even more preferably 1:1.
[0033] In this invention, the pressure of hydrogen gas introduced in step (1) is preferably 0.8 to 2.0 MPa, more preferably 1.2 to 1.8 MPa, and even more preferably 1.5 MPa.
[0034] In this invention, the flow rate of the N-benzylnebirol hydrochloride solution in step (1) is preferably 5 to 15 mL / min, more preferably 10 to 15 mL / min, and even more preferably 12 mL / min.
[0035] In this invention, the temperature of the hydrogenation reaction in step (1) is preferably 45-60°C, more preferably 50-60°C, and even more preferably 55°C; the time of the hydrogenation reaction in step (1) is preferably 1-5 min, more preferably 3-5 min, and even more preferably 3 min.
[0036] In this invention, the post-processing in step (2) is preferably cooling crystallization and filtration.
[0037] In this invention, the cooling crystallization temperature is preferably 15-20°C, more preferably 18-20°C, and even more preferably 20°C; the cooling crystallization time is preferably 0.5-1h, more preferably 0.8-1h, and even more preferably 1h.
[0038] This invention does not limit the filtering method; any method known to those skilled in the art is acceptable.
[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0040] Example 1
[0041] This embodiment provides a method for the continuous flow reaction synthesis of nebivolol hydrochloride, including the following steps, and the synthesis method flow is as follows: Figure 1 As shown:
[0042] (1) Add 20g of N-benzylnebivolol hydrochloride, 300mL of methanol and 20mL of water to the reaction flask, stir at 20℃ to dissolve, and prepare N-benzylnebivolol hydrochloride solution for later use;
[0043] (2) 16g of flake palladium on carbon (manufacturer: Shaanxi Ruike New Material Co., Ltd., effective substance content: 0.8wt%) was packed into the packed bed of a continuous flow fixed bed reactor (manufacturer: Shandong Weijing Chemical Technology Co., Ltd., model: VFBXSS0800); the air in the reactor was first replaced with nitrogen, and then hydrogen stored in the tank was continuously introduced into the reactor at a pressure of 1.0MPa; the temperature of the reactor was set to 50℃, and when the temperature reached 50℃ and remained constant, the pump speed was adjusted to 10mL / min, and N-benzyl nebirol hydrochloride solution was pumped into the reactor at this speed for hydrogenation reaction for 3min;
[0044] (3) Collect the effluent from the hydrogenation reaction, cool the effluent to 20°C and stir for 1 hour, then filter to obtain nebivolol hydrochloride. The reactions that occurred are as follows: Figure 2 As shown.
[0045] The solid nebivolol hydrochloride obtained in Example 1 was tested and found to contain only 0.04 wt% of raw material residue, with no detectable impurities (defluorination impurities), and the target product was 99.85 wt%, with a raw material conversion rate of 98.2%.
[0046] Example 2
[0047] This embodiment provides a method for the continuous flow reaction synthesis of nebivolol hydrochloride, including the following steps:
[0048] (1) Add 20g of N-benzylnebivolol hydrochloride, 300mL of methanol and 20mL of water to the reaction flask, stir at 20℃ to dissolve, and prepare N-benzylnebivolol hydrochloride solution for later use;
[0049] (2) 20g of flake palladium on carbon (manufacturer: Shaanxi Ruike New Material Co., Ltd., effective substance content: 1.0wt%) was packed into the packed bed of the continuous flow fixed bed reactor (manufacturer: Shandong Weijing Chemical Technology Co., Ltd., model: VFBXSS0800); the air in the reactor was first replaced with nitrogen, and then hydrogen stored in the tank was continuously introduced into the reactor at a pressure of 1.2MPa; the temperature of the reactor was set to 55℃, and when the temperature reached 55℃ and remained constant, the pump speed was adjusted to 12mL / min, and N-benzyl nebirol hydrochloride solution was pumped into the reactor at this speed for hydrogenation reaction for 3min;
[0050] (3) Collect the effluent after the hydrogenation reaction is completed, cool the effluent to 20°C and stir for 1 hour, then filter to obtain nebivolol hydrochloride.
[0051] The solid nebivolol hydrochloride obtained in Example 2 was tested and found to contain only 0.02 wt% of raw material residue, with no detectable impurities (defluorination impurities), and the target product was 99.86 wt%, with a raw material conversion rate of 98.5%.
[0052] Comparative Example 1
[0053] (1) Add 20g N-benzylnebirol hydrochloride, 300mL methanol, 20mL water and 1.5g palladium on carbon (manufacturer: Shaanxi Ruike New Material Co., Ltd., effective substance content: 10wt%) to the high-pressure reactor, start stirring, purge with nitrogen 3 times, then fill the high-pressure reactor with 1.0MPa hydrogen, set the external temperature to 50℃, the internal pressure of the reactor to 1.5MPa, and react for 1h;
[0054] (2) After the reaction is complete, filter to remove the palladium on carbon catalyst. Transfer the filtrate to a 500 mL reaction flask, turn on the stirrer, cool to 20 °C, and keep stirring at 20 °C for 1 h. Solid precipitates out. Filter to obtain nebivolol hydrochloride.
[0055] The solid nebivolol hydrochloride obtained in Comparative Example 1 was tested and found to contain 0.32 wt% of raw material residue, 0.53 wt% of impurities (defluorination impurities), and 98.95 wt% of the target product, with a raw material conversion rate of 96.9%.
[0056] Compared with the reaction in a continuous flow reactor (Examples 1-2), the material obtained by the reaction in a conventional high-pressure reactor (Comparative Example 1) showed a significant detection of defluorination impurities. Furthermore, the subsequent purification process had a weaker ability to remove these impurities, making them difficult to completely eliminate. The raw material residue was slightly higher, and the conversion rate was slightly lower.
[0057] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A process for the continuous flow reaction synthesis of nebivolol hydrochloride, characterized in that, Includes the following steps: (1) A catalyst is packed into the packed bed of a continuous flow fixed bed reactor, hydrogen is introduced into the continuous flow fixed bed reactor, and N-benzylnebirol hydrochloride solution is added to carry out a hydrogenation reaction. (2) Collect the liquid after the hydrogenation reaction is completed, and perform post-treatment on the liquid to obtain nebivolol hydrochloride; Wherein, the N-benzyl nebirol hydrochloride solution in step (1) is a mixture of N-benzyl nebirol hydrochloride, a straight-chain monohydric alcohol and water; the straight-chain monohydric alcohol is methanol; the mass-volume ratio of the N-benzyl nebirol hydrochloride, the straight-chain monohydric alcohol and the water is 20g:200~300mL:20mL; The catalyst in step (1) is flake-shaped palladium on carbon, and the effective substance content of the catalyst in step (1) is 0.8~1.5 wt%. In step (1), the mass ratio of N-benzylnebirolol hydrochloride to catalyst in the N-benzylnebirolol hydrochloride solution is 1:0.5~1:1.2; The pressure of the hydrogen gas introduced in step (1) is 0.8~2.0 MPa; The temperature of the hydrogenation reaction in step (1) is 45~60℃, and the time of the hydrogenation reaction in step (1) is 1~5min.
2. The method for synthesizing nebivolol hydrochloride via continuous flow reaction as described in claim 1, characterized in that, The flow rate of the N-benzylnebirol hydrochloride solution in step (1) is 5~15 mL / min.
3. The method for synthesizing nebivolol hydrochloride via continuous flow reaction as described in claim 1, characterized in that, The post-processing described in step (2) is cooling crystallization and filtration.
4. The method for synthesizing nebivolol hydrochloride via continuous flow reaction as described in claim 3, characterized in that, The cooling crystallization temperature is 15~20℃, and the cooling crystallization time is 0.5~1h.
5. The method for continuous flow reaction synthesis of nebivolol hydrochloride as described in claim 1, characterized in that, Before introducing hydrogen into the continuous flow fixed bed reactor in step (1), the process also includes replacing the air in the continuous flow fixed bed reactor with nitrogen.